Infection with HIV leads to a chronic immune dysfunction characterized by lymphocyte hyperactivation and a gradual decline in CD4+ T cell populations. We and others have recently demonstrated that a small but potent specialized T cell subset, called natural killer T (NKT) cells, are selectively depleted in HIV infected individuals and are highly susceptible to infection in vitro. NKT cells are thought to be pivotal in modulating the responses of conventional lymphocytes by forming a bridge between innate and adaptive immune responses. Our central hypothesis is that perturbation of NKT cells by HIV contributes to the inadequate control of the infection and the progression to immunodeficiency in infected individuals. In more recent preliminary studies we have also found a highly potent anti-HIV activity displayed by dendritic cell-activated human NKT cells. Based on this finding and the published reports demonstrating that NKT cells can greatly amplify the response of conventional lymphocytes in an "adjuvant-like" activity, we hypothesize that NKT cells can be exploited in the formulation of new HIV vaccines. To test these hypotheses, experiments are proposed in highly integrated specific aims to: 1) delineate the activation requirements and mechanisms of depletion of NKT cells during HIV infection, 2) elucidate the molecular mechanisms of NKT cell anti-HIV activity, and test whether such activity is present in HIV infected individuals who suppress viral replication, 3) determine the mechanisms of NKT cell depletion and their potential as a vaccine adjuvant in an in vivo non-human primate model of HIV infection. We anticipate that the proposed studies will establish a framework to decipher the role of NKT cells in the matrix of HIV-host interactions. Moreover, the knowledge gained from our results could enable mobilization of potent NKT cell effector functions to potentiate antigen-specific immune responses or to directly suppress viral replication. This knowledge can lead to novel therapeutic and vaccine strategies against HIV infection aimed at manipulating the innate and adaptive arms of the immune response.